This invention relates to a process for continuously producing alkylpyrophosphonates, alkylpyrophosphates and multimers thereof and in particular for producing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and salts thereof, where the end product is obtained in particularly pure form and at high yields in a continuous reaction.
It is known according to U.S. Pat. No. 4,407,761 to Henkel Kommanditgesellschaft to prepare 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid with phosphonating reactants and then quenching the reaction mixture by the addition of a strong non-oxidizing agent, preferably concentrated hydrochloric acid, with heating, to hydrolyze the formed phosphorous intermediates to final product. However, this phosphonation reaction does not remain homogeneous, thereby producing heterogeneous solidification of the reaction mixture. This solidification causes variable yields and leads to the development "hot spots" which in part result from the exothermic nature of the reaction. Moreover, to make the sodium salt, using the prior art processes, requires isolation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and an additional step to convert this to the monosodium salt. Further, the use of concentrated hydrochloric acid in the quench, whose fumes present an environmental problem, is also required.
U.S. Pat. No. 4,922,007 to G. R. Kieczykowski, et al., (assigned to Merck & Co., Inc.) discloses the use of methanesulfonic acid to overcome the non-homogeneity and solidification problems associated with the formation of intermediates during the bisphosphonation phase. However, this process utilizes a non-pH controlled water quench that leads to the presence of a strongly acidic and corrosive hydrolysis mixture which requires specialized equipment.
U.S. Pat. No. 5,019,651 to G. R. Kieczykowski, et al., (assigned to Merck & Co., Inc.), discloses using a pH controlled quench step in the range of 4 to 10, followed by hydrolysis, that eliminates the concentrated hydrochloric acid formed in the quench step and the need to handle a corrosive acidic product hydrolysis mixture.
Prior methods teach the requirement that the reaction be completed at temperatures above the boiling point of PCl.sub.3, for instance 90.degree. C. However, this temperature is known to be in the adiabatic self-heat range that is an unsafe operating range as batch volumes increase and available cooling capacity decreases. In addition, control of stoichiometric ratio is important to achieving useful intermediates. However, control of stoichiometric ratios at constant temperature, typically 90.degree. C., is impossible using prior batch methods because stoichiometric quantities of PCl.sub.3 may only be added at sub reflux temperatures. For example, in U.S. Pat. No. 5,019,651, stoichiometric ratios were achieved by use of temperature programming whereby the stoichiometric amount of PCl.sub.3 could be added at sub-reflux temperatures. Alternatively, in U.S. Pat. No. 4,407,761, PCl.sub.3 was added slowly at isothermal reaction temperatures above PCl.sub.3 's boiling point. Thus, it is desirable to control both stoichiometry and reaction temperature at the same time to provide consistent distribution of useful intermediates and to ensure a safe operating environment. The prior batch modes of operation made control of stoichiometric ratios impossible while maintaining a constant temperature.
The present invention solves both of these problems through operation of the reaction in a continuous stirred tank reactor that allows greater heat transfer for temperature control while maintaining constant stoichiometric ratios of reactants. The more favorable surface to volume ratio of the present invention allows greater heat transfer for temperature control. Further, continuous steady operation results in fixed ratios of products and intermediates in a small controllable environment by controlling both reaction temperature and stoichiometric ratio at all times. The smaller reacting mixture reduces severity of an unexpected thermal event and allows the entire reacting mixture to be quenched.